Using genome sequencing to find the cause of undiagnosed rare conditions affecting bowel, heart, lung or brain in adults

Details

In the UK, a rare condition is one that affects fewer than 1/2000 people. Around 70% of rare conditions have a genetic cause (ie are caused by a change in a gene or piece of missing chromosome). Exome and genome sequencing have revolutionised diagnosis of the causes of rare conditions in children. Exome/genome sequencing read the code of all 20 000 genes, and can diagnose the cause of a rare condition in around 30% of children. The role of these types of testing is not well established in adults with rare conditions. The student will use exome and genome sequencing to identify the cause of rare conditions in adults.

The student will focus on people over the age of 16 years old, who have not had a cause for their condition identified using standard first line tests. Presentations of interest will be either severe diseases in single organ systems or multi-system medical conditions.

Firstly, the student will analyse exome data from our Sheffield clinical cohort of around 100 undiagnosed adult patients recruited via our specialist genetics clinic and also use the Genomics England research environment to analyse genome sequencing data from undiagnosed adult patients in the 100 000 genomes project.

Secondly, the student will undertake a prospective study of exome/genome sequencing in newly identified adult patients with rare diseases. The student would expand the study to investigate patients recruited via specialist adult medicine clinics such as gastroenterology (severe inflammatory bowel disease), endocrinology and respiratory clinic. We would aim to recruit around 100 patients over the 3-year PhD. This would enable us to calculate the diagnostic utility of this form of testing in this patient group. 

The student will receive full training in bioinformatic analysis of exome or genome sequencing. Genetic variants will be classified as benign or pathogenic using the American college of medical genetics criteria.  Relevant functional studies to help classify variants will be used for example RNA sequencing on blood samples to confirm splicing defects.  If genetic variants in potential novel disease genes are identified the student will use the genomics England research environment to try and identify other patients with the diagnosis. 

Depending on students preferences wet lab work could be undertaken to investigate the mechanism of any genetic variants identified.   For example studies of mitochondrial function in patient derived cells or or studies of human brain tissue from our local brain bank to examine Gene and protein expression

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. (add any additional requirements here)

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Enquiries:

Interested candidates should in the first instance contact

Dr Alisdair McNeill [email protected]

Proposed start date – October 2024